PROJECT SUMMARY Women are twice more likely than men to be diagnosed with depression, and depression is more severe and associated with greater functional impairment in women. However, the neurobiological underpinnings of this increased female susceptibility to depression are unknown. The dopamine (DA) system has traditionally been associated with anhedonia, the inability to derive pleasure from normally rewarding stimuli, and has been recently implicated in the pathophysiology in depression. Importantly, anhedonia is a core symptom of depression and other psychiatric diseases involving DA system dysregulation and characterized by substantial sex differences in their prevalence and nature, such as schizophrenia and drug addiction. Indeed, recent evidence has demonstrated a causal link between a hypofunctioning DA system (i.e. decreased DA neuron activity) and depression-related behaviors (i.e. anhedonia, despair). Surprisingly, little is known about DA system function in females. Thus, characterizing baseline DA system function, as well as stress-induced alterations within this system, is an essential step in understanding sexual dimorphism in the etiology of depression and other psychiatric disorders. Moreover, given the strong link between the DA system and depression, there is a significant potential benefit from novel interventions targeting DA system dysfunction in depression. In sum, the purpose of this proposal is threefold: 1) to define baseline behavioral and DA system function in male and female rats 2) to compare stress-induced behavioral and VTA DA neuron adaptations in male and female rats and 3) to identify potential pathways mediating susceptibility to stressors (i.e. acute, chronic) that differentially impact females. Our overarching hypothesis is that females are more susceptible to the deleterious effects of stress on behavior and VTA activity, and that these effects are mediated by decreased compensation (i.e. activity) in the vSub-NAc pathway. To test this, we will use an integrated systems-oriented approach focused on behavioral assays in vivo electrophysiology, chemogenetics. In this way, we hope to provide a unique perspective on the regulation of the DA system in males and females, the role of the DA system in stress-induced depressive-like symptomatology (i.e. anhedonia, despair), and the mechanisms underlying modulation of the DA system in both sexes under baseline conditions, following acute stress (i.e. post-FST) and after UCMS. Ultimately, these findings could shed light on the increased female vulnerability to depression and lead to the development of novel treatment strategies for depression and other psychiatric disorders implicating aberrant DA system function and anhedonia.